Project Summary/Abstract Both endogenous and exogenous interferon (IFN)-? suppress experimental autoimmune encephalomyelitis (EAE) in mice and multiple sclerosis (MS) in humans through poorly defined mechanisms. Still, IFN-? non- responders can be identified in both diseases. The transcription factor, IFN regulatory factor-7 (IRF7), is a key regulator of type-I IFN production in vivo. Genetic data have linked IRF gene polymorphisms with MS, including one case where the disease-associated variant correlated with a failure to induce multiple known IFN response genes following the initiation of IFN-? therapy. We find that IRF7-deficient mice develop more severe EAE than wild-type controls, and that levels of the chemokine, C-X-C motif chemokine ligand 13 (CXCL13), are abnormally high in IRF7-deficient mice both at baseline and in the spinal cord during EAE. Prior studies demonstrate that CXCL13 sustains myelin-specific CD4+ T cell responses and clinical symptoms during disease. Taken together, these data lead us to hypothesize that IRF7/type-I IFN acts to suppress lymphoid cell production of CXCL13 (or to prevent the emergence of CXCL13-producing lymphoid cells) as an adaptive mechanism to limit pathogenic CNS inflammation during EAE. We will test our hypothesis via two specific aims: 1) To clarify how IRF7 constrains encephalitogenic Th17 cells and suppresses adoptive transfer EAE via actions in the recipient host, and 2) To confirm the heightened susceptibility of IRF7-deficient mice to EAE is causally related to altered expression of CXCL13, and to investigate how CXCL13 acts to sustain EAE severity. Our main objective is to further characterize the role of IRF7 during CNS autoimmune demyelinating disease and to more directly link the actions of IRF7 and type-I IFN with lymphoid chemokine production. Our long-term goal is to better understand how IFN-? is efficacious in EAE and MS, and to develop methods to quickly identify MS patients who will be IFN-? non-responders so that alternative treatments can be initiated without delay. IFN-? remains the most commonly prescribed therapy for RRMS and will continue to be used for many years to come, so it remains incumbent to understand its actions in this disease.